In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood.
A cancer may have as many as 500 different dysregulated genes. The dysregulation of various genes may occur over a period as long as 20-30 years before a given cancer begins to manifest its symptoms. Therefore, targeting or inhibiting a single gene product or cell signaling pathway is unlikely to prevent or destroy cancer. Chemotherapy and specific targeted drugs have been developed to disrupt these gene products or pathways, thereby inducing cell death and impeding progression of malignant changes in cells. However, problems such as ineffective targeting and drug resistance have plagued these agents, necessitating changes in the approach to systemic cancer therapy. The current paradigm of cancer chemotherapy is either combinations of several drugs or a drug that modulates multiple targets. The combination chemotherapy approach uses drugs with different mechanisms of action to increase cancer killing. Various drugs that modulate multiple targets, have been approved by the U.S. Food and Drug Administration (FDA) for treatment of various cancer types. However, these drugs are costly, have a long list of undesirable side effects, and most of them are still not effective enough to have a significant effect on the course of the disease.
Targeted therapies should attack simultaneously different pathways in order to be more efficient. In practice, this goal is difficult to achieve for several reasons: new drugs are extremely expensive, their full pattern of side-effects and interference is incompletely known and it is difficult to get different drug companies to cooperate in combination clinical trials. Moreover, regulatory authorities (FDA and EMEA) require that a new drug proves its efficacy in monotherapy clinical trials and hence synergy of two drugs, which on their own are ineffective, is missed. On the other hand, there is broad recognition that multiple cross-covering growth promoting signaling pathways and cell death avoiding mechanisms are active in cancer cells. On the basis of pre-clinical results, there have been some attempts to treat cancer patients with compositions including melatonin and calciferol derivatives. However, these two molecules together did not show sufficient efficacy in clinical trials or only showed some effect in association to many other compounds, including chemotherapeutic drugs. Similarly, curcumin has been considered as anticancer agent. However, the required blood levels were of 10 μM, which is nearly impossible to obtain in human clinical condition.